S-triazolo (4,3-d) (1,4) benzodiazepin-6(7H)-ones

ABSTRACT

S-triazolo(4,3-d)(1,4)benzodiazepin-6(7H)-ones, e.g., 10-chloro7-methyl-3-(o-chlorophenyl)-5H-s-triazolo(4,3d)(1,4)benzodiazepin -6(7H)-one are prepared from a corresponding 1,4-benzodiazepin-2-one, and are useful as anti-convulsants and minor tranquilizers.

Unite States Patent [191 Kathawala Mar. 4, 1975 S-TRIAZOLO (4,3-D) 1,4)

BENZODlAZEPIN-6(7H)-ONES [75] Inventor: Faizulla G. Kathawala, WestOrange, NJ.

[73] Assignee: Sandoz-Wander, Inc., Hanover, NJ.

[22] Filed: June 18, 1973 [21] Appl. No.1 370,917

[52] 11.5. CI. 260/2393 T, 424/269 [5 1] Int. Cl.. C07d 53/06, C07d55/00, C07d 99/02 [58] Field of Search 260/2393 T Primary Examiner-HenryR. Jiles Assistant E.\'aminer-Robert T. Bond Attorney, Agent, orFirm-Gerald D. Sharkin; Richard E. Vila; Joseph J. Borovian [57]ABSTRACT 7 Claims, N0 Drawings where:

R and'R, each independently represent hydrogen, halo having an atomicweight of about 18 to 80, lower alkyl, i.e. alkyl having 1 to 4 carbonatoms, eg. methyl, ethyl, propyl, isopropyl and the like,

nitro or trifluoromethyl provided that at least one R and R, is halo,preferably chloro, when R is hydrogen; and

R is hydrogen, lower alkyl asdefined above; and

R is hydrogen, lower alkyl as defined above; unsubstituted phenyl orphenyl mono-substituted with halo having an atomic weight of 18 to 80,and

R, is hydrogen, and

R,-, is unsubstituted phenyl or phenyl monosubstituted ordi-substitutetl with halo having an atomic weight of 18 to 80.

The compounds of formula (l) may be prepared by the following reactionscheme where Z is lower alkyl of l to 2 carbon atoms, and

where R,, R R R and R,-, are as defined above.

The compounds of formula (I) are prepared by treating a compound of theformula (II) with an acylhydrazide ofthe formula (III) in an inertorganic solvent such as ethers, e.g., diethyl-ether, glyme, di-glyme ortetrahydrofuran, preferably di-glyme. The reaction temper ature is notcritical, but it is preferred that the reaction be carried out betweenabout 30 to 180C, especially the reflux temperature of the solvent. Thereaction is typically run from about to 28 hours. The compounds offormula (I) may be recovered using conventional techniques, e.g,crystallization.

Certain of the compounds of formula (II) and (III) are known and may beprepared by methods disclosed in the literature. Those compounds of theformulae (II) and (III) not specifically disclosed may be prepared byanalagous methods from known starting materials.

The compounds of formula (I) possess pharmacological activity. Inparticular they possess minor tranquil- V izer and anti-convulsantactivity as indicated (1) by their ability to produce docility inbehavior tests in mice given 50 to 250 mg/kg i.p. of the test compoundaccording to the 30-word adjective check sheet system,

basically described by S. Irwin Gordon Research Conference, MedicinalChemistry, 1959 and Chem. Symposium on Sedative and Hypnotic Drugs,Williams and Williams 1954, and (2) by their ability to antagonizechronic convulsions and death in mice given 50 to 250 mg/kg, i.p. of thetest compound followed one hour later by 50 mg/kg i.p. ofN-sulfamoylazepine.

For such usage, the compounds of formula (I) may be administered orallyor parenterally as such or admixed with conventional pharmaceuticalcarriers. They may be administered orally in such forms as tablets,dispersible powders, granules, capsules, syrups and elixirs, andparenterally as solutions eg., a sterile injectable aqueous solution.The compositions for oral use may contain one or more conventionaliadjuvants, such as sweetening agents, flavoring agents, coloring agentsand preserving agents, in order to provide an elegant and palatablepreparation. Tablets may contain the active ingredient in admixture withconventional pharmaceutically acceptable exicpients, e.g., inertdiluents, such as calcium carbonate, sodium carbonate, lactose, andtalc, granulating and distintegrating agents, eg., starch and alginicacid, binding agents, eg., starch, gelatin and acacia, and lubricatingagents, eg., magnesium stearate, steaic acid and talc. The tablets maybe uncoated or coated by known techniques to delay disintegration' andabsorption in the gastrointestinal tractand thereby provide a sustainedaction over a longer period. Similarly, suspensions, syrups, andelixirs, may contain the active ingredient in admixture with any of theconventional excipients utilized for the preparation of suchcompositions, c.g., suspending agents (lecithin, polyoxyethylenestearate and polyoxyethylene sorbitan hydroxybenzoate). Capsules maycontain the active ingredient alone or admixed with an inert soliddiluent,

eg., calcium carbonate, calcium phosphate and kaolin.

The injectable compositions are formulated as known in the art. Allthese pharmaceutical preparations may contain up to about of the activeingredient in combination with the carrier or adjuvant.

Furthermore, the compounds of formula (I) may be similarly administeredin theform of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly, are included within the scope of the invention.Representative ofthe acid addition salts are the mineral acid salts,such as the hydrochloride, hydrobromide, sulfate and phosphate and thelike and the organic acid salts such as succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate, and the like.

For the above use as a minor tranquilizer and an anticonvulsant, thedosage of compound (I) will vary depending upon themode ofadministration utilized and uid pharmaceutical carrier or diluent.

Tablets and capsules containing the ingredients indicated below may beprepared by conventional techd.7-methyl-l0-trifluoromethyl-3-(o-chlorophenyl)- 5H-s-triazolo[4,3- d][l,4]benzodiazepin-6(7H)-one,

lO-chloro-S,7-dimethyl-3-(o-chlorophenyl)-5H-striazolo[4,3-d][l.4]benzodiazepin-6(7H)-one, or f.lO-chloro-7-methyl-5-phenyl-3-(o-chlorophenyl)- 5H-s-triazolo[4,3-d lllt4]benzodiazepin-Z-one. respectively. Also following the aboveprocedure and using in place of o-chlorobenzoyl hydrazide an equivalentamount of 2,6-dichlorobenzoyl hydrazide there is-obtained I a.l0-chloro-7-methyl-3-(2,6-dichlorophenyl)-5H-striazolo[4,3-d][ l,4]benzodiazepin-6( 7H )-one f. 3-phenyl- 1 -methyl- 1,3-dihydro-5-ethoxy-7-chloro- (2H)-l.4-benzodiazepin-2-one there isobtained a. V 7.l0-dimethyl-3-(o-chlorophenyl)-5H-striazolol 4.3-d][ 1,4]benzodiazepin-6( 7H )-one. b.7-methyl-3-(o-chlorophenyl)-5H-s-triazolo[4 3- d H IAlbenzodiazepin-(v(7H )-one.

7-methyl-lO-nitro-3-(o-chlorophenyl)-5H-striazolol4,3-d][l,4}benzodiazepin-6( 7H)-one,

niques and are useful in effecting tranquilization at a Wh i l i d idose of one tablet or capsule 2 to 4 times a day. 1 A u d f th f lIngredients Weight (mg) tablet capsulelO-chloro-7-methyl-3-(o-chlorophenyl)-5H-5- triazolol4,3-d][l,4]benzodiazepin-6(7H)-one 200 200 tragacanth l0 lactose 247.5 300 cornstarch talcum l5 magnesium stearate 2.5 Total 500 mg 500 mg EXAMPLE 1l0-chloro-7-methyl-3-(o-chlorophenyl)-5H-striazolol[4,3-d][l,4]benzodiaZepin-6(7H )-one.

A mixture of 2.5 grams of l,3-dihydro-l-methyl-5-ethoxy-7-ehloro-(2H)-l,4-benzodiaZepin-2-one and 2 grams ofo-chlorobenzoyl hydrazide is refluxed in 100 ml. ofdiglyme for 7 hoursand then stirred at room temperature for 18 hours. The solvent isremoved in vacuo and the resulting residue is treated with water,satu- Irated with solid sodium chloride and extracted several Wheremi timeswith ethyl acetate. The combined ethyl acetate 0 and 1 Eachindependently represent hydrogen, extracts are washed once with water,dried over anhyhalo having an atomic Weight of about 13 t0 drous sodiumsulfate, filtered and evaporated in vacuo alkyl 0f 1 t0 4 Carbon atoms,or trlfluoro' to give lO-chloro-7-methyl-3-(o-chlorophenyl)-5H-smethylProvided that. at least of R0 and 1 is triazolo[4,3-d][ 1,4]benzodiazepin-6(7H)-one m.p. halo, preferably Chloro. when 2 18hydrogen; and 70 175 R is hydrogen, alkyl of lto 4 carbon atoms, and

Following the above procedure and using in place of a is y g alkyl of 1t0 4 Carbon atoms unsubl,3-dihydro-l-methyl-5-ethoxy-7-chloro-(2H)-1,4-stituted phenyl or phenyl mono-substituted with benzodiazepin-Z-one anequivalent amount of halo ing an atomic gh of 18 IO 80 a.1,3-dihydro-5-ethoxy-l,7-dimethyl-(2H)-l ,4- 4 is y g andbenzodiazepin2-one, R is unsubstituted phenyl or phenyl monob.l,3-dihydro-l-methyl-5-ethoxy-(2H)-1,4- substituted or disubstitutedwith halo having an benZQdiaZ i -Z- e, atomic weight of 18 to 80, or apharmaceutically c. l,3-dihydro-l-methyl-5-ethoxy-7-nitro-(2H)-l ,4- asacceptable acid addition salt thereof. benzodiazepin-Z-one, 2. Acompound of claim 1 in free base form. d.l,3-dihydro-l-methyl-5-ethoxy-7-trifluoromethyl- 3. A compound of theformula (2H l ,4-benzodiazepin-2-one, e.1.3-dimethyl-l,3-dihydro-5-ethoxy-7-chloro-(2H)- CH1,4-benzodiazepin-2-one, or o where:

R and R are as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof. 4. A compound of the formula where:

R R and R- are as defined in claim 1, or a pharmaceutically acceptableacid addition salt thereof. 5. A compound of the formula with a compoundof the formula in an inert organic solvent where Z represents loweralkyl of l to 2 carbon atoms, and

R0, R, R R3, R and R are as defined in claim 1.

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 in free base form.3. A compound of the formula
 4. A compounD of the formula
 5. A compoundof the formula
 6. The compound of claim 1 which is10-chloro-7-methyl-3-(o-chlorophenyl)-5H-s-triazolo(4,3-d)(1,4)benzodiazepin-6(7H)-one.
 7. A process for preparing a compound of claim1 which comprises the step of reacting a compound of the formula